Upregulation of protein kinase cdelta in vascular smooth muscle cells promotes inflammation in abdominal aortic aneurysm.
BACKGROUND
The development of abdominal aortic aneurysms (AAAs) involves a complex interplay of extracellular matrix degradation, inflammation, and apoptosis. We have previously shown that protein kinase Cdelta (PKCdelta) plays a critical role in vascular smooth muscle cell (vSMC) apoptosis in the setting of oxidative stresses. Here, we show that PKCdelta is also involved in the signaling that draws inflammatory cells to aneurismal tissue.


METHODS
Immunostaining for monocyte chemotactic factor (MCP)-1 and PKCdelta was performed on paraffin-fixed arterial sections. Enzyme-linked immunosorbent assay to detect MCP-1 produced by vSMCs was performed on media from cultured rat A10 cells after cytokine induction with or without the PKCdelta-specific inhibitor rottlerin. Migration of isolated lymphocytes was evaluated in response to media from activated A10 cells.


RESULTS
Human AAAs show widespread and elevated expression of PKCdelta that is not seen in normal aortic tissues. Cytokine stimulation of cultured vSMCs induced vigorous production of the key chemotactant MCP-1, the expression of which was PKCdelta dependent. Stimulated vSMCs were capable of inducing the migration of leukocytes, and this effect was also dependent on PKCdelta activity. Staining of human AAA tissue for MCP-1 showed an expression pattern that was identical to that of PKCdelta and smooth muscle specific alpha-actin.


CONCLUSIONS
PKCdelta is widely expressed in human AAA vessel walls and mediates MCP-1 expression by vSMCs, which could contribute to the inflammatory process. These findings, coupled with earlier studies of PKCdelta, suggest that PKCdelta plays a central role in the pathogenesis of AAAs and may be a potential target for future therapies.
Schubl
Sebastian
S
Department of Surgery, Division of Vascular Surgery, New York Presbyterian Hospital, and Weill Medical College of Cornell University, New York, New York 10021, USA.
Tsai
Shirling
S
Ryer
Evan J
EJ
Wang
Chunjie
C
Hu
June
J
Kent
K Craig
KC
Liu
Bo
B
D000818:Animals; D001012:Aorta, Abdominal / Q000378:metabolism; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism*; D001025:Aortitis / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
C111835:CCL2 protein, human; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D051745:Protein Kinase C-delta